U.S. Pat. No. 5,057,614 to Davis, et. al., describes substituted pyrrole compounds of formula I:
wherein R1 signifies hydrogen, alkyl, aryl (limited to phenyl), aralkyl (limited to phenylalkyl), alkoxyalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, aminoalkylaminoalkyl, azidoalkyl, acylaminoalkyl, acylthioalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl, alkylsulphonyloxyalkyl, alkylcarbonyloxyalkyl, cyanoalkyl, amidinoalkyl, isothiocyanatoalkyl, glucopyranosyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, hydroxyalkylthioalkyl, mercaptoalkylthioalkyl, arylthioalkyl or carboxyalkylthioalkyl or a group of the formula—(CH2)n—W-Het,   (a)—(CH2)n—T—C(═V)—Z,   (b)—(CH2)n—NH—C(═O)—lm, or  (c)—(CH2)n—NH—C(═NH)—Ar   (d)in which Het signifies a heterocyclyl group, W signifies NH, S or a bond, T signifies NH or S, V signifies O, S, NH, NNO2, NCN OR CHNO2, Z signifies alkylthio, amino, monoalkylamino or dialkylamino, lm signifies 1-imidazolyl, Ar signifies aryl, and n stands for 2-6; R2 signifies hydrogen, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylsulphinyl; R3 signifies a carbocyclic or heterocyclic aromatic group; R4, R5, R6 and R7 each independently signify hydrogen, halogen, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl or alkylsulphonyl; and one of X and Y signifies O and the other signifies O, S, (H,OH) or (H,H); with the proviso that R1 has a significance different from hydrogen when R2 signifies hydrogen, R3 signifies 3-indolyl or 6-hydroxy-3-indolyl, R4, R5 and R7 each signify hydrogen, R6 signifies hydrogen or hydroxy and X and Y both signify O and when R2 signifies hydrogen, R3 signifies 3-indolyl, R4, R5, R6 and R7 each signify hydrogen, X signifies (H,H) and Y signifies O; as well as pharmaceutically acceptable salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids, as therapeutically active substances for the use in control or prevention of inflammatory, immunological, bronchopulmonary and cardiovascular disorders.
The novel compounds of the present invention are structurally unlike those disclosed by the Davis U.S. Pat. No. 5,057,614. In particular, the Davis U.S. Pat. No. 5,057,614 discloses indolyl substituted pyrrole compounds of formula I which may be further substituted on the R3 position with a carbocyclic or heterocyclic aromatic group. The carbocyclic aromatic group denoted by R3 can be a monocyclic or polycyclic group, preferably a monocyclic or bicyclic group, i.e. phenyl or naphthyl, which can be substituted or unsubstituted, for example, with one or more, preferably one to three, substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl and alkylsulphonyl. Unlike compounds of the present invention, examples of carbocyclic aromatic groups denoted in the Davis '614 patent by R3 are phenyl, 2-, 3-, or 4-chlorophenyl, 3-bromophenyl, 2- or 3-methylphenyl, 2,5-dimethylphenyl, 4-methoxyphenyl, 2- or 3-trifluoromethylphenyl, 2-, 3-, or 4-nitrophenyl, 3-, or 4-aminophenyl, 4-methylthiophenyl, 4-methylsulphinylphenyl, 4-methylsulphonylphenyl and 1-, or 2-naphthyl. The heterocyclic aromatic group denoted by R3 can be a 5- or 6-membered heterocyclic aromatic group which can optionally carry a fused benzene ring and which can be substituted or unsubstituted, for example, with one or more, preferably one to three, substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, mono- or dialkylamino, alkylthio, alkylsulphinyl and alkylsulphonyl. Unlike compounds of the present invention, examples of heterocyclic aromatic groups denoted in the Davis '614 patent by R3 are 2-, or 3-thienyl, 3-benzothienyl, 1-methyl-2-pyrrolyl, 1-benzimidazolyl, 3-indolyl, 1- or 2-methyl-3-indolyl, 1-methoxymethyl-3-indolyl, 1-(1-methoxyethyl)-3-indolyl, 1-(2-hydroxypropyl)-3-indolyl, 1-(4-hydroxybutyl)-3-indolyl, 1-[1-(2-hydroxyethylthio)ethyl]-3-indolyl, 1-[1-(2-mercaptoethylthio)ethyl]-3-indolyl, 1-(1-phenylthioethyl)-3-indolyl, 1-[1-(carboxymethylthio)ethyl]-3-indolyl and 1-benzyl-3-indolyl.
U.S. Pat. No. 5,721,245 to Davis, et. al., describes substituted 4-[3-indolyl]-1H-pyrrolone compounds of formula I:
wherein R is hydrogen or hydroxy, R1 and R2 taken together are a group of the formula —(CH2)n— and R7 is hydrogen or R1 and R7 taken together are a group of the formula —(CH2)n— and R2 is hydrogen; R3 is an aryl or aromatic heterocyclic group; R4, R5 and R6 each independently are hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl or alkylsulfonyl; R8 is a group of the formula —(CH2)p—R9 or —(CH2)q—R10; R9 is hydrogen, alkylcarbonyl, aminoalkylcarbonyl, cyano, amidino, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, aminocarbonyl or aminothiocarbonyl; R10 is hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkylsulfonylamino, arylsulfonylamino, alkylthio, alkoxycarbonylamino, aminoacylamino, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulfonyloxy or arylsulfonyloxy, a 5- or 6-membered saturated nitrogen-containing heterocycle attached via the nitrogen atom or a group of the formula —U—C(V)—W; U is S or NH; V is NH, NNO2, NCN, CHNO2; W is amino, monoalkylamino or dialkylamino; one of X and Y is O and the other is O or (H,H); Z is CH or N; m, p and q are, independently, an integer from 0 to 5, and n is an integer from 1 to 5, with the proviso that q and m are, independently, 2 to 5 when Z is N; as well as pharmaceutically acceptable salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids, as therapeutically active substances for use in control or prevention of inflammatory, immunological, bronchopulmonary and cardiovascular disorders.
The novel compounds of the present invention are structurally unlike those disclosed by the Davis U.S. Pat. No. 5,721,245. In particular, the Davis U.S. Pat. No. 5,721,245 discloses 4-[3-indolyl]-1H-pyrrolone compounds of formula I which may be further substituted on the R3 position with an aryl or aromatic heterocyclic group. The term “aryl”, alone or in combination denotes a monocyclic or polycyclic group, preferably a monocyclic or bicyclic group, for example, phenyl or naphthyl, which can be substituted or unsubstituted, for example, with one or more, preferably one to three, substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl and alkylsulfonyl. Unlike compounds of the present invention, examples of such aryl groups in the Davis '245 patent are phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 2-methylphenyl, 3-methylphenyl, 2,5-dimethylphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 4-aminophenyl, 4-methylthiophenyl, 4-methylsulfinylphenyl, 4-methylsulfonylphenyl, 1-naphthyl, 2-naphthyl and the like. The term “aromatic heterocyclic” means a 5- or 6-membered heterocyclic aromatic group which can optionally carry a fused benzene ring and which can be substituted or unsubstituted, for example, with one or more, preferably one to three, substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl and alkylsulfonyl. Unlike compounds of the present invention, examples of such heterocyclic groups in the Davis '245 patent are 2-thienyl, 3-thienyl, 3-benzothienyl, 3-benzofuranyl, 2-pyrrolyl, 3-indolyl and the like which can be unsubstituted or substituted in the manner indicated. The 5- or 6-membered saturated nitrogen containing heterocycle attached via the nitrogen atom can contain an additional nitrogen or oxygen or a sulfur atom, examples of such heterocycles are pyrrolidino, piperidino, piperazino, morpholino and thiomorpholino.
U.S. Pat. No. 5,624,949 to Heath, Jr., et. al., describes bis-indolemaleimide derivatives of the formula:
wherein W is —O—, —S—, —SO—, —SO2—, —CO—, C2-C6 alkylene, substituted alkylene, C2-C6 alkenylene, -aryl-, -aryl(CH2)mO—, -heterocycle-, -heterocycle-(CH2)mO—, -fused bicyclic-, -fused bicyclic-(CH2)mO—, —NR3—, —NOR3—, —CONH— or —NHCO—; X and Y are independently C1-C4 alkylene, substituted alkylene, or together, X, Y and W combine to form (CH2)n-AA-; R1 is independently hydrogen, halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, haloalkyl, nitro, NR4R5 or —NHCO(C1-C4)alkyl; R2 is hydrogen, CH3CO—, NH2 or hydroxy; R3 is hydrogen, (CH2)maryl, C1-C4 alkyl, —COO(C1-C4 alkyl), —CONR4R5, —C(C═NH)NH2, —SO(C1-C4 alkyl), —SO2(NR4R5) or —SO2(C1-C4 alkyl); R4 and R5 are independently hydrogen, C1-C4 alkyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring; AA is an amino acid residue; m is independently 0, 1, 2 or 3; and n is independently 2, 3, 4 or 5 as protein kinase C (PKC) inhibitors and as selective PKCβ-I and PKCβ-II inhibitors.
Patent application WO 00/06564 discloses disubstituted maleimide compounds of Formula (I):
wherein R1 represents hydrogen or alkyl; R2 represents aryl, cycloalkyl or a heterocycle; R3, R5, R6, R7 and R8 represent each hydrogen, halogen, hydroxy, amino, alkyl or alkoxy; and R4 is W, or R4 and R3 or R4 and R5 may form together a ring substituted by W thereon; wherein W represents —(CH2)l—(Y)m—(CH2)n-Z as PKCβ inhibitors.
Patent application WO 00/21927 describes 3-amino-4-arymaleimide compounds having formula (I):
or a pharmaceutically acceptable derivative thereof, wherein: R is hydrogen, alkyl, aryl or aralkyl; R1 is hydrogen, alkyl, aralkyl, hydroxyalkyl or alkoxyalkyl; R2 is substituted or unsubstituted aryl or substituted or unsubstituted heterocyclyl; R3 is hydrogen, substituted or unsubstituted alkyl, cycloalkyl, alkoxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl or aralkyl wherein the aryl moiety is substituted or unsubstituted; or, R1 and R3 together with the nitrogen to which they are attached form a single or fused, optionally substituted, saturated or unsaturated heterocyclic ring and a method for the treatment of conditions associated with a need for inhibition of GSK-3, such as diabetes, dementias such as Alzheimer's disease and manic depression.
The indazolyl-substituted pyrroline compounds of the present invention have not been heretofore disclosed.
Accordingly, it is an object of the present invention to provide indazolyl-substituted pyrroline compounds useful as a kinase or dual-kinase inhibitor (in particular, a kinase selected from protein kinase C or glycogen synthase kinase-3; and, more particularly, a kinase selected from protein kinase C α, protein kinase C β (e.g. protein kinase C β-I and protein kinase C β-II), protein kinase C γ or glycogen synthase kinase-3β), methods for their production and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.